Astagraf XL

"Analysis of three biomarkers in the urine of kidney transplant recipients can diagnose — and even predict — transplant rejection, according to results from a clinical trial sponsored by the National Institute of Allergy and Infect"...

Clinical Studies Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice. In addition, the
clinical trials were not designed to establish comparative differences across
study arms with regards to the adverse reactions discussed below.

The data described below reflect exposure to ASTAGRAF XL
in 545 renal transplant recipients exposed to ASTAGRAF XL for periods up to two
years [see Clinical Studies].

Study 1: With Basiliximab Induction

The proportion of patients who discontinued treatment due
to adverse reactions was 9% in the ASTAGRAF XL arm and 11% in the Prograf
control arm through 12 months of treatment. The most common adverse reactions
leading to discontinuation in ASTAGRAF XL-treated patients were related to
infections or renal/urinary disorders. The most common ( ≥ 30%) adverse
reactions observed in the ASTAGRAF XL group were: diarrhea, constipation,
nausea, peripheral edema, tremor and anemia.

Study 2: Without Induction

The proportion of patients who discontinued treatment due
to adverse reactions was 13% in the ASTAGRAF XL arm and 11% in the Prograf
control arm through 12 months of treatment. The most common adverse reactions
leading to discontinuation in ASTAGRAF XL-treated patients were related to
infections, graft dysfunction, renal vascular/ischemic conditions and diabetes.
The most common ( ≥ 30%) adverse reaction observed in the ASTAGRAF XL group
was anemia.

New Onset Diabetes After Transplant (NODAT)

New onset diabetes after transplantation (defined by the
composite occurrence of ≥ 2 fasting plasma glucose values that were >
126 mg/dL at ≥ 30 days apart, insulin use for ≥ 30 consecutive
days, oral hypoglycemic use for ≥ 30 consecutive days, and/or HbA1C ≥
6.5%) is summarized in Table 2 below for Study 1 and Study 2 through one year
post-transplant.

Table 2: Composite NODAT Through 1 Year
Post-Transplant in Studies 1 and 2

Study 1

Study 2

ASTAGRAF XL
n (%)
(N=162)

Prograf
n (%)
(N=151)

ASTAGRAF XL
n (%)
(N=288)

Prograf
n (%)
(N=299)

Composite NODAT

58 (36)

53 (35)

105 (37)

90 (30)

≥ 2 Fasting Plasma Glucose Values ≥ 126 mg/dL ≥ 30 days apart

42 (26)

35 (23)

51 (18)

47 (16)

Insulin use ≥ 30 consecutive days

10 (6)

12 (8)

29 (10)

29 (10)

Oral hypoglycemic use ≥ 30 consecutive days

22 (14)

13 (9)

20 (7)

23 (8)

HbA1C ≥ 6.5%

31 (19)

33 (22)

48 (17)

39 (13)

Infections

Adverse reactions of infectious
etiology were reported based on clinical assessment by physicians. The causative
organisms for these reactions are identified when provided by the physician.
The overall number of infections, serious infections, and select infections
with identified etiology reported in patients treated with ASTAGRAF XL or the
control in Studies 1 and 2 are shown in Table 3.

Table 3: Overall Infections and Select Infections by
Treatment Group in Studies 1 and 2 Through One Year Post-Transplant

Study 1

Study 2

ASTAGRAF XL
n (%)
(N=214)

Prograf
n (%)
(N=212)

ASTAGRAF XL
n (%)
(N=331)

Prograf
n (%)
(N=336)

All Infections

148 (69)

146 (69)

228 (69)

216 (64)

Serious Infections

48 (22)

49 (23)

79 (24)

64 (19)

Bacterial Infections

18 (8)

25 (12)

125 (38)

137 (41)

Respiratory Infections

73 (34)

65 (31)

75 (23)

74 (22)

Cytomegalovirus Infections

21 (10)

24 (11)

38 (12)

21 (6)

Polyomavirus Infections

6 (3)

10 (5)

7 (2)

1 (0)

Gastroenteritis

16 (7)

6 (3)

16 (5)

8 (2)

Studies 1 and 2 were not
designed to support comparative claims for ASTAGRAF XL for the adverse
reactions reported in this table.

Glomerular Filtration Rate

The estimated mean glomerular
filtration rates, using the Modification of Diet in Renal Disease (MDRD)
formula, by treatment group at Month 12 in the ITT population in Studies 1 and
2 are shown in Table 4.

a Subject's last observation carried forward (LOCF) for
missing data at Month 1; patients who died, lost the graft or were lost to
follow-up are imputed as zeroes b Tacrolimus XL-Prograf treatment mean difference results of
analysis of covariance model with Month 1 Baseline as a covariate.

The incidence of adverse
reactions that occurred in ≥ 15% of ASTAGRAF XL-treated patients compared
to control through one year of treatment in Studies 1 and 2 are shown in Table
5.

Skin and Subcutaneous Tissue Disorders

Vascular Disorders

Postmarketing Experience

The following adverse reactions have been reported from
worldwide marketing experience with tacrolimus. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.

DRUG INTERACTIONS

Since tacrolimus is metabolized mainly by CYP3A enzymes,
drugs or substances known to inhibit these enzymes may increase tacrolimus
whole blood concentrations. Drugs known to induce CYP3A enzymes may decrease
tacrolimus whole blood concentrations [see WARNINGS AND PRECAUTIONS, CLINICAL
PHARMACOLOGY]. Dose adjustments may be needed along with frequent
monitoring of tacrolimus whole blood trough concentrations when ASTAGRAF XL is
administered with CYP3A inhibitors or inducers. In addition, patients should be
monitored for adverse reactions including changes in renal function and QT
prolongation [see WARNINGS AND PRECAUTIONS].

Mycophenolic Acid Products

With a given dose of mycophenolic acid (MPA) products,
exposure to MPA is higher with ASTAGRAF XL coadministration than with
cyclosporine coadministration because cyclosporine interrupts the enterohepatic
recirculation of MPA while tacrolimus does not. Clinicians should monitor for
MPA associated adverse events and reduce the dose of concomitantly administered
mycophenolic acid products, if needed.

Alcohol

Consumption of alcohol with ASTAGRAF XL may increase the
rate of release of tacrolimus and/or adversely alter the pharmacokinetic
properties and the effectiveness and safety of ASTAGRAF XL. Therefore,
alcoholic beverages should not be consumed with ASTAGRAF XL [see DOSAGE AND
ADMINISTRATION].

Protease Inhibitors

Most protease inhibitors inhibit CYP3A enzymes and may increase
tacrolimus whole blood concentrations. It is recommended to avoid concomitant
use of tacrolimus with nelfinavir unless the benefits outweigh the risks [see CLINICAL
PHARMACOLOGY]. Whole blood concentrations of tacrolimus are markedly increased
when coadministered with telaprevir or with boceprevir. Monitoring of
tacrolimus whole blood concentrations and tacrolimus-associated adverse
reactions, and appropriate adjustments in the dosing regimen of tacrolimus are
recommended when tacrolimus and protease inhibitors (e.g., ritonavir,
telaprevir, boceprevir) are used concomitantly.

Antifungal Agents

Frequent monitoring of whole blood concentrations and
appropriate dosage adjustments of tacrolimus are recommended when concomitant
use of the following antifungal drugs with tacrolimus is initiated or
discontinued [see CLINICAL PHARMACOLOGY].

Azoles: Voriconazole, posaconazole, itraconazole,
ketoconazole, fluconazole and clotrimazole inhibit CYP3A metabolism of
tacrolimus and increase tacrolimus whole blood concentrations. When initiating
therapy with voriconazole or posaconazole in patients already receiving
tacrolimus, it is recommended that the tacrolimus dose be initially reduced to
one-third of the original dose and the subsequent tacrolimus doses be adjusted
based on the tacrolimus whole blood concentrations.

Caspofungin is an inducer of CYP3A and decreases whole
blood concentrations of tacrolimus.

Calcium Channel Blockers

Verapamil, diltiazem, nifedipine, and nicardipine inhibit
CYP3A metabolism of tacrolimus and may increase tacrolimus whole blood
concentrations. Monitoring of whole blood concentrations and appropriate dosage
adjustments of tacrolimus are recommended when these calcium channel blocking
drugs and tacrolimus are used concomitantly.

Antibacterials

Erythromycin, clarithromycin, troleandomycin and
chloramphenicol inhibit CYP3A metabolism of tacrolimus and may increase
tacrolimus whole blood concentrations. Monitoring of blood concentrations and
appropriate dosage adjustments of tacrolimus are recommended when these drugs
and tacrolimus are used concomitantly.

Antimycobacterials

Rifampin [see CLINICAL PHARMACOLOGY] and rifabutin
are inducers of CYP3A enzymes and may decrease tacrolimus whole blood concentrations.
Monitoring of whole blood concentrations and appropriate dosage adjustments of
tacrolimus are recommended when these antimycobacterial drugs and tacrolimus
are used concomitantly.

Anticonvulsants

Phenytoin, carbamazepine and phenobarbital induce CYP3A
enzymes and may decrease tacrolimus whole blood concentrations. Monitoring of
whole blood concentrations and appropriate dosage adjustments of tacrolimus are
recommended when these drugs and tacrolimus are used concomitantly.

Concomitant administration of phenytoin with tacrolimus
may also increase phenytoin plasma concentrations. Thus, frequent monitoring of
phenytoin plasma concentrations and adjusting the phenytoin dose as needed are
recommended when tacrolimus and phenytoin are administered concomitantly.

St. John's Wort (Hypericum perforatum)

St. John's Wort induces CYP3A enzymes and may decrease
tacrolimus whole blood concentrations. Monitoring of whole blood concentrations
and appropriate dosage adjustments of tacrolimus are recommended when St.
John's Wort and tacrolimus are coadministered.

Gastric Acid Suppressors/Neutralizers

Lansoprazole and omeprazole, the proton pump inhibitors
(PPIs), as CYP2C19 and CYP3A4 substrates, share the same CYP3A4 system with
tacrolimus for their hepatic elimination, and may potentially competitively
inhibit the CYP3A4 metabolism of tacrolimus and thereby substantially increase
tacrolimus whole blood concentrations, especially in transplant patients who
are intermediate or poor CYP2C19 metabolizers in which the PPIs metabolic
pathway shifts from 2C19 to 3A4, as compared to those patients who are
efficient CYP2C19 metabolizers.

Cimetidine, a CYP2C19 and CYP3A4 inhibitor, may also
inhibit the CYP3A4 metabolism of tacrolimus and thereby substantially increase
tacrolimus whole blood concentrations.

Coadministration with magnesium and aluminum hydroxide
antacids increase tacrolimus whole blood concentrations. Monitoring of whole
blood concentrations and appropriate dosage adjustments of tacrolimus are
recommended when these drugs and tacrolimus are used concomitantly.

Other Drugs

Amiodarone, bromocriptine, nefazodone, metoclopramide,
danazol, ethinyl estradiol and methylprednisolone may inhibit CYP3A metabolism
of tacrolimus and increase tacrolimus whole blood concentrations. Monitoring of
blood concentrations and appropriate dosage adjustments of tacrolimus are
recommended when these drugs and tacrolimus are coadministered.

Last reviewed on RxList: 3/18/2014
This monograph has been modified to include the generic and brand name in many instances.